Recent Progress in Metastatic Breast Cancer:

Transcription

1 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy A CME-CERTIFIED ACTIVITY Medical Experts: Mohammad Jahanzeb, MD Medical Oncologist Professor of Clinical Medicine, Hematology-Oncology Medical Director, Deerfield Beach Campus University of Miami Sylvester Comprehensive Cancer Center Deerfield Beach, FL Denise A. Yardley, MD Medical Oncologist Senior Investigator, Breast Cancer Research Sarah Cannon Research Institute Tennessee Oncology, PLLC Nashville, TN Medical Writer: Jennifer Klem, PhD Physicians Education Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physicians Education Resource designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity is supported by an educational grant from Eisai Inc. To participate in this activity online, go to

2 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy Initial release date: July 15, 2013 Expiration date: July 15, 2014 Media used: Print monograph with online posttest, evaluation, and request for credit Estimated time to complete this CME activity: 1 hour Statement of Need An estimated 234,580 Americans will be diagnosed with breast cancer in Unfortunately, metastatic breast cancer (MBC) remains incurable, with a 24% 5-year survival rate, and it is the second leading cause of cancer deaths in women. The primary goals of treatment of MBC are to prolong overall survival while maximizing quality of life, delaying tumor progression, and preventing or palliating symptoms. However, the sheer number of potentially appropriate therapies for each individual patient can make choosing a treatment regimen daunting for oncologists. Classification of MBC by molecular subtypes, each of which requires a different treatment approach, further complicates treatment decision-making. In addition, staying current on the wealth of data from current clinical trials can be challenging. Thus, there is a significant educational need for oncologists to be familiar with current guidelines for management of MBC, evidence-based treatment options for each MBC subgroup, and emerging agents in late-stage clinical trials. Further, community oncologists can benefit from expert insights regarding the interpretation and application of these data to their everyday practices. Learning Objectives Review the current expert practice guidelines for MBC Evaluate cytotoxic treatment options for a patient with HER2- negative, hormone receptor-negative, or hormone-refractory MBC Analyze recent clinical trial data on novel treatments and emerging therapies for the management of MBC Target Audience This activity is designed to educate oncologists and oncology nurses on the optimal management of metastatic breast cancer. Oncologists, pathologists, and oncology nurses are involved in the care of patients with metastatic breast cancer. Oncologists diagnose and manage the treatment of patients with metastatic breast cancer. Oncology nurses oversee treatment administration and the day-to-day care of patients with breast cancer. Accreditation and Designation of Credit Statements Physicians Education Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physicians Education Resource designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Commercial Support Acknowledgment This activity is supported by an educational grant from Eisai Inc. Faculty Mohammad Jahanzeb, MD, FACP Medical Oncologist Professor of Clinical Medicine, Hematology-Oncology Medical Director, Deerfield Beach Campus Associate Center Director for Community Outreach University of Miami Sylvester Comprehensive Cancer Center Deerfield Beach, FL Denise A. Yardley, MD Medical Oncologist Senior Investigator, Breast Cancer Research Sarah Cannon Research Institute Tennessee Oncology, PLLC Nashville, TN Disclosure of Relevant Financial Relationships With Commercial Interests The following individual has relevant financial relationships with commercial interests to disclose: Mohammad Jahanzeb, MD, FACP, is a consultant for Genentech/Roche. The following individuals have no relevant financial relationships with commercial interests to disclose: Denise A. Yardley, MD; Jennifer Klem, PhD; and the PER Planning Staff (Susan Peck, PhD, and Wendy Ashmen). Off-Label/Investigational Use Disclosure and Disclaimers This CME activity contains the following references to investigational and/or off-label uses of drugs included but not limited to doxorubicin, epirubicin, pegylated liposomal doxorubicin,, paclitaxel, nab-paclitaxel, carboplatin, cisplatin, cyclophosphamide, capecitabine, gemcitabine, methotrexate, fluorouracil, vinorelbine, eribulin, ixabepilone, bevacizumab, NKTR- 102, NK012, tesetaxel, ramucirumab, sorafenib, and tivozanib. Uses of agents are not indicated by the FDA. The opinions expressed in the enduring activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient s medical condition. Method of Participation/How to Receive Credit In order to receive a CME certificate for this activity, participants must: 1. Read the monograph in its entirety. 2. Go to 3. Click on the Request CME Credits button, and login. If you do not have an existing PER account, click on Become a Member, register for an account, and then login. 4. Complete and submit the posttest, evaluation form, and request for credit. A passing score of 70% or higher is required to obtain a CME certificate. 5. Print your Certificate of Credit. Accredited Provider Contact Information: For questions about this CME activity, please contact: Physicians Education Resource, LLC 666 Plainsboro Road, Ste 356 Plainsboro, NJ Phone: (888) Copyright Physicians Education Resource

3 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy Medical Writer: Jennifer Klem, PhD Medical Reviewer: Mohammad Jahanzeb, MD INTRODUCTION Breast cancer is the most frequently diagnosed malignancy among women in the United States. 1 Survival of patients with breast cancer has improved in recent decades, from a 5-year relative survival of about 75% in to nearly 90% in , 2 largely due to earlier detection and improvements in treatment of early-stage disease. Unfortunately, metastatic breast cancer (MBC) remains incurable, and survival of advanced disease has improved less impressively over the past 30 years, with a most recent 5-year relative survival rate of only 24%. 1 Despite the modest overall survival (OS) improvement in the last three decades, there have been a number of agents that have improved progression-free survival (PFS) in these patients. Only 5% of the nearly 232,000 female patients diagnosed annually with breast cancer have metastatic disease at diagnosis, 1,2 but many more eventually develop MBC after being diagnosed with and treated for early-stage or locally advanced disease. Newer techniques for genomic analysis have enabled us to further subclassify breast cancer into many subtypes. Four of the major subtypes include luminal A, luminal B, basal-like, and HER2+/ER-/PR-. 3 They can also be clinically identified by assessing grade and surface markers such as hormonal receptor status (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 receptor status (Table 1). 4 The hormone receptor-rich luminal A subtype is the most common, with an incidence of 54% in one large study, and HER2+/ER-/PR- is the least common subtype, accounting for only 6% of all breast cancers; however, exact incidence can vary by racial/ethnic backgrounds. 5 Luminal A and B cancers have better prognoses and lower mortality rates than the triple-negative breast cancer (TNBC) and untreated HER2+/ER-/PR- subtypes (Table 1). 5 Table 1. Breast Cancer Subtype Phenotype 4 Breast Cancer Subtype ER/PR HER2 Ki-67 Current Clinical Practice Guidelines for the Management of MBC Because MBC is not curable at present, the goals of treatment are both to prolong survival and to improve patients quality of life by relieving cancer-related symptoms. Decisions about specific therapies for patients with MBC are made using a treatment algorithm that is based on the hormone receptor status and HER2 status; thus, treatment is functionally dependent upon the subtype of the tumor. In general, hormone receptor positive disease is treated with endocrine therapy, and hormone receptor negative disease is treated with chemotherapy, with or without the addition of HER2-directed agents, depending on HER2 status (Figure). Although targeted therapies are being investigated for TNBC and hormonal therapy refractory MBC, chemotherapy remains the mainstay of treatment today for this population of patients. (Recent approval of everolimus based on BOLERO-2 results is for a narrow subpopulation of hormone receptor positive postmenopausal women whose disease has progressed on prior nonsteroidal aromatase inhibitor therapy.) 6 The focus Figure. Treatment algorithm for metastatic breast cancer. (Red boxes designate the focus of this review article.) ER-positive and/or PR-positive Luminal A and Luminal B Endocrine therapy, until visceral crisis or no clinical benefit from 3 consecutive regimens ER-negative/PR-negative or hormone-refractory Luminal A + low Luminal B (HER2-negative) + high Luminal B (HER2-positive) + + any HER2-positive HER2+/ER-/PR - HER2-positive Triple-negative Basal-like (triple-negative) N/A HER2+ + N/A Chemotherapy + HER2-directed therapy Chemotherapy (± targeted therapies) ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; N/A = not applicable; PR = progesterone receptor. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor. A CME-Certified Activity Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy 1

4 Table 2. Chemotherapy Regimens For Patients with MBC, According to the NCCN Breast Cancer Clinical Practice Guidelines 7 Single Chemotherapy Agents Anthracyclines *doxorubicin *pegylated liposomal doxorubicin (PLD) epirubicin Antimetabolites *capecitabine *gemcitabine Taxanes *paclitaxel albumin-bound paclitaxel Other microtubule inhibitors *vinorelbine *eribulin ixabepilone Platinums carboplatin cisplatin Alkylating agent cyclophosphamide MBC = metastatic breast cancer. *preferred single agent Chemotherapy-Only Combination Regimens CAF/FAC: cyclophosphamide, doxorubicin, fluorouracil FEC: fluorouracil, epirubicin, cyclophosphamide AC: doxorubicin, cyclophosphamide EC: epirubicin, cyclophosphamide CMF: cyclophosphamide, methotrexate, fluorouracil GT: gemcitabine, paclitaxel XT:, capecitabine Gemcitabine, carboplatin of this review is on cytotoxic chemotherapy regimens for such patients. An abundance of chemotherapy regimens are available for the treatment of these patients; the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for breast cancer lists 14 single agents and eight combination regimens as acceptable choices (Table 2). 7 A number of factors should be considered when choosing the optimal regimen for each patient from the list of chemotherapy choices. The efficacy of the regimen is always of paramount importance, but all of the regimens in Table 2 have demonstrated efficacy in patients with MBC. However, there are differences to be noted. For instance, combination regimens generally have higher response rates and longer time to progression than single-agent therapy. 8 In contrast, single agents cause less toxicity than combination regimens 8 that can negatively impact efficacy. In some clinical trials, the addition of a second chemotherapy agent to a single agent has demonstrated a survival advantage 9,10 ; however, these trials have failed to address whether combination chemotherapy is superior to sequential single-agent therapy, since crossover upon progression to the newer agent from the standard single-agent arm was limited to 16%-17% of the patients. This raises the possibility that sequential singleagent therapy may be just as effective as the combination regimen. 11 In 2009, the European School of Oncology Metastatic Breast Cancer Task Force suggested that although either combination or sequential single-agent chemotherapy is a reasonable approach for first-line MBC, combination chemotherapy should be reserved for patients in acute visceral crisis who might benefit from an earlier rapid response. 11 Those patients with a short disease-free interval (DFI) after adjuvant therapy, 12 large tumor burden, rapid tempo of disease, or poor initial response to therapy may also receive benefit from combination chemotherapy. For all others, sequential single-agent therapy is the generally preferred approach. Another important factor in choosing a therapy for metastatic disease is the tolerability of the candidate regimens. Tolerability depends not just on the characteristics of the chemotherapy agent, but also on certain patient characteristics, including performance status, comorbidities, and, to some extent, age. For instance, single agents are preferred for patients with a poor performance status because they generally have fewer associated toxicities than combination regimens. In addition, specific comorbidities can contraindicate certain chemotherapy agents, such as congestive heart failure (CHF), precluding the use of anthracyclines due to their known cardiac toxicities. 13,14 Older patients frequently receive monotherapy because of tolerability concerns, despite the fact that no age-related trends in chemotherapy-related toxicity have been observed. 15 Some physicians, however, consider age to be less important than performance status and comorbidities, leading them to treat fit elderly patients with standard chemotherapy regimens. Patient preference also plays an important role in chemotherapy decisions. Patients may prioritize avoidance of certain toxicities, such as hair loss for emotional reasons or peripheral neuropathy because it would impair work or lifestyle activities. In addition, oral chemotherapy (eg, capecitabine) can be preferred by some patients, particularly those who have received prior oral endocrine therapy. Prior exposure to adjuvant therapy must be considered before choosing an MBC regimen. Anthracyclines and taxanes are the most active agents against breast cancer, and most patients with breast cancer treated in the United States have received adjuvant or neoadjuvant therapy that includes one or both of these agents. If patients have a DFI >12 months after receiving primary therapy with an anthracycline and/or a taxane, reintroduction of the same agent or regimen can be considered, if necessary, while keeping in mind the cumulative nature of their toxicities and the acceptable maximum total dose of anthracyclines. 16 In general, patients do not receive anthracyclines or taxanes as first-line MBC therapy unless they have not received them previously. 12 Table 3. Efficacy Results From Phase III Comparative Clinical Trials of Anthracyclines in MBC Study (author, year) Line of Therapy Arm 1 Arm 2 ORR (%) O Brien 2004 first line PLD doxorubicin 33% vs 38% Bontenbal 1998 second line epirubicin doxorubicin Italian Multicentre Breast Study 1988 any line FEC FAC 28% vs 36% (P =.17) 54% vs 57% (P =.47) Arm 1 vs Arm 2 Median TTP/PFS (months) 6.9 vs 7.8 HR = 1.00 (95% Cl, ) 4.4 vs 5.3 (P =.06) 9.0 vs 10.3 (P =.59) Median OS (months) 21 vs 22 HR = 0.94 (95% Cl, ) 10.2 vs 10.8 (P =.20) 19.4 vs 20.2 (P =.75) CI = confidence interval; FAC = fluorouracil, doxorubicin, cyclophosphamide; FEC = fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin; TTP = time to progression. 2 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy A CME-Certified Activity

5 Table 4. Cardiac Safety Results From Phase III Comparative Clinical Trials of Anthracyclines in MBC Study (author, year) Line of Therapy Arm 1 Arm 2 Classes of MBC Cytotoxic Therapies Subclinical Cardiotoxicity (%) Several classes of chemotherapy agents have demonstrated efficacy in breast cancer and are included in the NCCN guidelines for the treatment of MBC (Table 2): anthracyclines, antimetabolites, taxanes, other antimicrotubule agents, platinums, and alkylating agents. Characteristics of anthracyclines and some more recent drug classes and clinical trial results for some of the more commonly used key chemotherapy agents are discussed below. Arm 1 vs Arm 2 Clinical Cardiotoxicity (%) O Brien 2004 first line PLD doxorubicin 3.9% vs 14.9% 0% vs 3.9% Bontenbal 1998 Italian Multicentre Breast Study 1988 second line epirubicin doxorubicin NR 1.8 vs 7.8% any line FEC FAC NR 0.4% vs 1.6% FAC = fluorouracil, doxorubicin, cyclophosphamide; FEC = fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer; NR = not reported; PLD = pegylated liposomal doxorubicin. Anthracyclines In the United States, most patients have already been treated with an anthracycline in the adjuvant or neoadjuvant settings before developing MBC. However, approximately 5% of patients with breast cancer in the United States are diagnosed with de novo metastatic disease, 2 and for these patients anthracyclines are still a reasonable first-line treatment option. A retrospective pooled analysis of combination chemotherapy regimens suggested that anthracycline-containing regimens produce a modest OS advantage over other MBC chemotherapy regimens, although this benefit appears to be confined to those patients with HER2-positive disease. 17 Three anthracyclines (doxorubicin, epirubicin, and pegylated liposomal doxorubicin [PLD]) are in clinical use for the treatment of MBC. Doxorubicin was the first of the three agents to be used to treat cancer, 13 and the other two anthracyclines were developed in response to concerns about doxorubicin-related cardiotoxicity, discussed below. Three phase III MBC trials have compared the newer anthracyclines with doxorubicin in a randomized, controlled manner (Table 3) Each trial has reported similar efficacy outcomes for the anthracyclines tested, although across trials response rates have ranged from 28%-57%, median time to progression (TTP)/PFS from 4.4 to 10.3 months, and median OS from 10.2 to 22 months These ranges are likely due to differences in study populations. Caution must be exercised, however, when prescribing anthracyclines because these agents all carry a risk of cardiotoxicity. Cardiac concerns were first recognized with doxorubicin in the 1970s 13 ; during this time, CHF was discovered to occur at a frequency of 2.2% with doxorubicin use. 14 It was also discovered that the primary determinant of CHF development was a cumulative dose of doxorubicin 550 mg/m 2. 14,21 It was later demonstrated that subclinical changes in left ventricular ejection fraction (LVEF) were observed with doxorubicin doses as low as 350 mg/m An important characteristic of anthracycline-induced cardiotoxicity is that it typically appears after the completion of therapy, becoming apparent within one year with early-onset chronic cardiotoxicity, and many years later with late-onset chronic cardiotoxicity. 13 This makes it crucial to adhere to cumulative dosing guidelines (lifetime dose, mg/m 2 ), 21 since any damage caused from previous anthracycline exposure may not be apparent for years to come, and to assess cardiac function before and after therapy. Two phase III trials have compared epirubicin regimens to doxorubicin regimens, and in both cases, epirubicin demonstrated less cardiotoxicity Table 5. Efficacy Results From Randomized Comparative Clinical Trials of Taxanes in MBC Arm 1 vs Arm 2 Study (author, year) Arm 1 Arm 2 ORR (%) Median TTP/PFS (months) Median OS (months) Jones mg/m 2 q3wk paclitaxel 175 mg/m 2 q3wk 32% vs 25% (P =.10) 5.7 vs 3.6 (P <.0001) 15.4 vs 12.7 (P =.03) Gradishar 2005 nab-paclitaxel 260 mg/m 2 q3wk paclitaxel 175 mg/m 2 q3wk 33% vs 19% (P =.001) 5.3 vs 3.9 (P =.006) 15.0 vs 12.9 (P =.4) *Gradishar 2009 *Gradishar 2012 nab-paclitaxel 150 mg/m 2 weekly 100 mg/m 2 q3wk 49% vs 35% (P = NS) 12.9 vs 7.5 (P =.007) 33.8 vs 26.6 (HR =.69) **Rugo ASCO 2012 (CALGB 40502) nab-paclitaxel 150 mg/m 2 weekly + bevacizumab paclitaxel 90 mg/m 2 weekly + bevacizumab NR 9.2 vs 10.6 (P =.1) 27 vs 26 (P =.9) MBC = metastatic breast cancer; NR = not reported; NS = not significant; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; q3wk = every 3 weeks; TTP = time to progression. *This trial had two other nab-paclitaxel arms (300 mg/m 2 q3wk; 100 mg/m 2 weekly) that were less efficacious than 150 mg/m 2 weekly. **The trial had an ixabepilone + bevacizumab arm, which is presented in Table 11. A CME-Certified Activity Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy 3

6 Table 6. Safety Results From Randomized Comparative Clinical Trials of Taxanes in MBC Study (author, year) Grade 3/4 Adverse Events (%) Nab-paclitaxel 260 mg/m 2 q3wka 150 mg/m 2 weekly b Docetaxel 100 mg/m 2 q3wk Jones 2005 c neutropenia 93% febrile neutropenia 15% asthenia 21% stomatitis 11% infection 10% neurosensory 7% peripheral edema 7% Gradishar 2005 ac neutropenia 31% leukopenia 6% sensory neuropathy 10% Gradishar 2012 b neutropenia 45% sensory neuropathy 22% fatigue 4% *Rugo ASCO 2012 bd neutropenia 47% leukopenia 17% sensory neuropathy 25% fatigue 16% (Table 4). 19,20 This may be due to small structural differences of epirubicin compared with doxorubicin, which allow for the rapid metabolism of the drug. 23 The reduced cardiotoxicity of both epirubicin (OR = 0.39; 95% confidence interval [CI], ) and PLD (OR = 0.18; 95% CI, ) in comparison with doxorubicin has been confirmed by a meta-analysis of 55 randomized controlled trials examining anthracyclines. 24 Only one phase III trial has compared PLD with doxorubicin, but both subclinical and clinical cardiotoxicity were clearly reduced in the PLD arm (3.9% vs 14.9% and 0% vs 3.9%, respectively). 18 The liposomal delivery of PLD, which reduces the amount of free doxorubicin, not only reduces cardiotoxicity but also improves drug penetration and decreases drug clearance. 25 Taxanes Taxanes are among the most effective classes of chemotherapy agents in the treatment of breast cancer. They work by premature polymerization and hyperstabilization of the mitotic spindle, which ultimately blocks mitosis and induces cell death. 26 Paclitaxel, which is widely used in breast cancer as a single agent and as a part of combination therapies, was approved by the FDA in It is indicated for use in patients who have relapsed within 6 months after adjuvant therapy or who progressed after combination chemotherapy for metastatic disease. 27 Docetaxel was approved in 1996 as a single agent for MBC after chemotherapy failure, 28 and an albumin-bound form of paclitaxel, nab-paclitaxel, was approved in 2005 for the same indication as paclitaxel. 29 Nab-paclitaxel is the only taxane formulation that is solvent-free (paclitaxel is formulated with Cremophor and with polysorbate 80), thereby avoiding solventrelated hypersensitivity reactions without the need for premedication. 30 Efficacy results from four head-to-head trials conducted to compare the currently available taxanes are outlined in Table 5. In a phase III trial against paclitaxel, achieved superior efficacy outcomes, with significantly improved median TTP (5.7 months vs 3.6 months) and median OS (15.4 months vs 12.7 months). 31 However, as discussed Paclitaxel 175 mg/m 2 q3wk c 90 mg/m 2 weekly d neutropenia 55% febrile neutropenia 2% asthenia 5% stomatitis 0% infection 2% neurosensory 4% peripheral edema 1% neutropenia 46% leukopenia 8% sensory neuropathy 2% neutropenia 92% sensory neuropathy 12% fatigue 19% q3wk = every 3 weeks *This trial also had an ixabepilone arm, which is included in Table 11. All arms included bevacizumab. below, proved more toxic, including higher rates of grade 3/4 neutropenia (93% vs 55%) and febrile neutropenia (15% vs 2%) (Table 6). In two of the three comparative nab-paclitaxel trials, this solvent-free taxane had similar or better efficacy outcomes than the other taxanes, demonstrating a significantly better response rate (14% absolute improvement) and median TTP (1.4-month improvement) than paclitaxel 32 and a significant 5.4-month improvement in TTP and a 7.2-month improvement in OS compared with that did not reach statistical significance (Table 5). 33,34 In the trial comparing nab-paclitaxel with, three different dosages and schedules of nab-paclitaxel were examined: an every-3-week regimen (300 mg/m 2 ) and two weekly regimens (100 mg/m 2 and 150 mg/ m 2 ). The 150-mg/m 2 weekly dose produced somewhat better outcomes than the other two schedules without significantly sacrificing tolerability. 33 However, only one phase III trial compared weekly nab-paclitaxel with weekly paclitaxel, and it produced different efficacy results from the other randomized trials. In this CALGB trial, the two weekly taxanes were combined with bevacizumab (a third arm combining ixabepilone with bevacizumab will be discussed in a later section). Nab-paclitaxel did not retain its apparent efficacy advantage over paclitaxel, demonstrating a 9.2-month median PFS compared with 10.6 months (P =.12) and a median OS that was not significantly different from the paclitaxel arm (27 vs 26 months; P =.92). 35 As shown in Table 6, the most common grade 3/4 toxicity with was neutropenia, with >90% of patients experiencing this adverse event (AE). 31,34 Febrile neutropenia, a serious AE that typically requires hospitalization, occurred in 15% of patients receiving in one of the studies. 31 Although peripheral neuropathy is a well-established AE of paclitaxel, 27 the studies in Table 6 reported 25% of patients with grade 3/4 levels of this toxicity (neurosensory, sensory neuropathy). 31,32,35 This may be explained by the fact that patients with pre-existing neuropathy ( grade 1 in one study; grade 2 in the others) were excluded from enrollment. 31,32,35 These trials did report a relatively high incidence of all grades of neuropathy, as demonstrated by 59% incidence of neurosensory AEs and 13% incidence of neuromotor AEs with paclitaxel in the head-tohead trial with. 31 When compared with every-3-week taxanes, weekly nab-paclitaxel appeared to have favorable safety results. However, CALGB 40502, which compared weekly schedules of nab-paclitaxel with paclitaxel, showed no tolerability advantage for nab-paclitaxel. 35 The primary advantages of nab-paclitaxel are the avoidance of need for premedications to prevent hypersensitivity reactions and shorter infusion times. It is also postulated that neuropathy induced by nab-paclitaxel is shorterlived compared with that induced by solvent-based paclitaxel. Nonetheless, taken together, neither efficacy nor safety results from these randomized trials make nab-paclitaxel the obvious choice. As previously mentioned, patients who develop MBC after adjuvant therapy have typically already received a taxane. Although patients who relapse after treatment have generally been considered resistant to that treatment, this belief has recently been called into question. A German 4 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy A CME-Certified Activity neutropenia 18% leukopenia 7% sensory neuropathy 16% fatigue 9%

7 Table 7. Efficacy Results From Phase III Antimetabolite Combination Chemotherapy Clinical Trials in MBC Study (author, year) Nielsen 2011 Albain 2008 Martin 2007 O Shaughnessy 2002 Pallis 2012 Seidman 2011 Mavroudis 2010 Sparano 2010 Chan 2009 Thomas 2007 Antimetabolite Combination gemcitabine + gemcitabine + paclitaxel gemcitabine + vinorelbine capecitabine + gemcitabine + vinorelbine gemcitabine + capecitabine + capecitabine + ixabepilone gemcitabine + capecitabine + ixabepilone Comparator Arm paclitaxel vinorelbine ORR (%) 36% vs 34% (P =.78) 41% vs 26% (P =.0002) 36% vs 26% (P =.09) 42% vs 30% (P =.006) capecitabine 28% vs 24% (P =.006) capecitabine + epirubicin + capecitabine capecitabine + capecitabine 35% vs 41% (P =.24) 53% vs 51% (P =.8) 43% vs 29% (P <.0001) 32% vs 32% 35% vs 14% (P <.0001) Antimetabolite Combo vs Comparator Arm Median TTP/PFS (months) 10.3 vs 8.3 (P =.06) 6.1 vs 4.0 (P =.0002) 6.0 vs 4.0 (P =.003) 6.1 vs 4.2 (P =.0001) 5.4 vs 5.2 (P =.7) 9.3 vs 8.9 (P =.4) 11.0 vs 10.6 (P =.7) 6.2 vs 4.4 (P =.0005) 8.1 vs 8.0 (P =.1) 5.8 vs. 4.2 (P =.0003) Median OS (months) 19.7 vs 17.9 (P =.6) 18.6 vs 15.8 (P =.049) 15.9 vs 16.4 (P =.8) 14.5 vs 11.5 (P =.01) 20.4 vs 22.4 (P =.3) 23.0 vs 23.3 (P =.8) 35.7 vs 37.6 (P =.7) 16.4 vs16.5 (P =.1) 19.3 vs 21.5 (P = 1) NR Combo = combination; MBC = metastatic breast cancer; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TTP = time to progression. Blue text denotes trials that addressed whether an antimetabolite added to a microtubule agent could produce a survival benefit. Other trials compared an antimetabolite + a microtubule agent to either an antimetabolite monotherapy or to another antimetabolite/microtubule agent combination. Bold text denotes efficacy results in antimetabolite-containing arms. trial called the Taxane Re-Challenge Cohort Study 36 retrospectively examined 106 patients with recurrent disease who had been treated with a taxane as part of neoadjuvant or adjuvant therapy, and were later treated for MBC with a taxane-containing regimen. Nearly half of these patients (48.6%) achieved at least a partial response to first-line therapy, with 27% having a complete response. This suggests that taxane resistance did not develop in many of these patients. Moreover, outcome to taxane retreatment improved with an increase in the DFI after initial taxane treatment. Thus, patients with a DFI >12 months after receiving primary therapy with a taxane may benefit from rechallenge with that taxane, 16 but caution should be exercised if these patients have unresolved peripheral neuropathy since that is a cumulative toxicity that could worsen with additional taxane exposure. 37 Antimetabolites Antimetabolites are drugs that disrupt the normal metabolic processes within a cell, ultimately inhibiting cell growth and division. They have been used since 1948 against various types of cancer. Two antimetabolites capecitabine and gemcitabine were approved for use in breast cancer in 1998 and 2004, respectively. As a class, antimetabolites are a popular choice among patients with breast cancer because they rarely cause alopecia. 38,39 Capecitabine, a prodrug of 5-fluorouracil, is often a favored therapy because it is administered orally. Capecitabine is approved for use in combination with in patients who have already received an anthracycline, and as monotherapy in patients who have already received paclitaxel and an anthracycline. 38 Gemcitabine is most effective when administered with a taxane in the first- or second-line setting, although it is only approved with paclitaxel as frontline therapy in patients who have already received an anthracycline but not a taxane. 39 No head-to-head trials have been conducted comparing capecitabine monotherapy with gemcitabine monotherapy in MBC, although two randomized trials of capecitabine plus versus gemcitabine plus reported strikingly similar outcomes between the arms in the first-line MBC setting 40,41 (Table 7). A number of phase III first-line MBC trials have also examined the efficacy and safety of these antimetabolite monotherapy regimens in a controlled setting, showing that both agents are active in this patient population (Table 8). The capecitabine monotherapy arms demonstrated a consistent 21%-26% response rate and a median TTP/PFS ranging from 5.7 months to 7.1 months, except for one trial that included only those patients with rapidly progressive disease. As would be expected, those patients showed predictably shorter median PFS and OS times 45 compared with the other trial results. The only phase III trial of gemcitabine monotherapy produced a 16% response rate and a 3.4-month median TTP in patients age 60 years or older. 46 Although these antimetabolites have demonstrated similar efficacy, they do have distinct safety profiles, despite some overlap of toxicities. Examination of the safety results from one of the capecitabine phase III trials capecitabine vs cyclophosphamide/methotrexate/fluorouracil (CMF) reveals that the most common capecitabine-associated toxicities are fatigue, nausea, hand-foot syndrome, and diarrhea, 43 and this is consistent with what has been observed in other trials with capecitabine. The gemcitabine trial did not report all grades of toxicities, but the most common grade 3/4 toxicities were neutropenia, leukopenia, thrombocytopenia, and nausea/vomiting. 46 The toxicity differences of these agents allow patients and physicians to choose an antimetabolite that has the most favorable safety profile for a particular patient. Antimetabolite-containing combination regimens have also been wellstudied in the first-line MBC setting (Table 7). In all of these trials, an antimetabolite was paired with a microtubule agent, most often a taxane. Capecitabine combinations produced response rates of 32%-53%, medi- A CME-Certified Activity Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy 5

8 Table 8. Efficacy Results From Phase III First-Line Antimetabolite Clinical Trials in MBC Study (author, year) Antimetabolite Comparator Arm Jäger 2010 capecitabine PLD 24% vs 23% (P =.9) Robert 2011 capecitabine capecitabine + bevacizumab Jassem 2012* capecitabine capecitabine + xabepilone ORR (%) 24% vs 35% (P =.01) Antimetabolite vs Comparator Arm Median TTP/PFS (months) 7.1 vs 6.2 (P =.3) 5.7 vs 8.6 (P <.001) 24% vs 46% 2.8 vs 5.6 (P <.0001) Stockler 2011 capecitabine CMF 21% vs 18% 6.0 vs 7.0 (P =.2) Feher 2005 gemcitabine epirubicin 16% vs 40% (P <.001) 3.4 vs 6.1 (P =.0001) CMF = cyclophosphamide, methotrexate, fluorouracil; MBC = metastatic breast cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin; TTP = time to progression. *rapidly progressing disease Bold text denotes efficacy results in antimetabolite monotherapy arms. Median OS (months) 29.4 vs 22.4 (P =.44) 22.8 vs 25.7 (P =.3) 12.5 vs 15.1 (P =.2) 22.0 vs 18.0 (P =.02) 11.8 vs 19.1 (P =.0004) an TTP/PFS of 5.8 months to 11.0 months, and median OS of 14.5 months to 35.7 months. Gemcitabine combinations produced similar outcomes, with response rates of 28%-41%, median TTP/PFS of 5.4 months to 10.3 months, and median OS of 15.9 months to 23.0 months. A subset of these trials (denoted in blue in Table 7) addressed whether the addition of an antimetabolite to a microtubule agent (eg, paclitaxel ± gemcitabine) could improve survival. Two of these four trials produced a significant survival benefit of approximately 3 months, 9,10 whereas the other two demonstrated no significant difference between arms 47,48 (Table 7). The two trials showing a survival advantage were not able, however, to provide insight as to how combination therapy compared with sequential single-agent therapy because neither used a crossover design. Thus, although these trials appear to support combination therapy over monotherapy, they cannot rule out the possibility that sequential single-agent therapy is at least as efficacious as combination treatment. In fact, the E1193 trial, which is the only randomized trial to address this question with a mandatory crossover in the two single-agent arms to the alternate agent, demonstrated an improved response rate with combination therapy but similar survival between arms, showing that combination therapy did not provide a survival benefit over sequential single-agent therapy. 49 Table 9. Vinorelbine Treatment Results From Clinical Trials in MBC Endpoint Efficacy Phase II Fumoleau 1993 N=157 Phase II Women 60 Years Vogel 1999 N=56 Phase III Vinorelbine vs Gemcitabine/Vinorelbine Martin 2007 N=252 Median PFS 5.8 months 6 months 4.0 vs 6.0 months (P =.003) Median OS 16.8 months NR 16.4 vs 15.9 months (P =.8) ORR 41% 38% 26% vs 36% (P =.09) Safety Most common AEs from vinorelbine monotherapy arm Most common grade 3/4 AEs from vinorelbine monotherapy arm neutropenia 97% granulocytopenia 92% anemia 76% alopecia 35% nausea/emesis 30% granulocytopenia 72% neutropenia 54% anemia 5% neutropenia 95% granulocytopenia 93% anemia 89% elevated AST 51% nausea 43% granulocytopenia 80% neutropenia 61% febrile neutropenia 11% anemia 7% asthenia 7% AEs = adverse events; MBC = metastatic breast cancer; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival. Bold text denotes efficacy results in vinorelbine monotherapy arms. NR neutropenia 44% alopecia 17% fatigue 15% febrile neutropenia 6% Other microtubule agents Aside from taxanes, other chemotherapy drugs also target microtubules to disrupt cell growth and proliferation. Vinorelbine, a vinca alkaloid, is frequently used in the treatment of relapsed/refractory MBC. Vinorelbine depolymerizes the microtubule assembly, thereby preventing cell division. 50 Results from one phase III trial 47 and two phase II studies 51,52 examining vinorelbine monotherapy in patients with MBC are presented in Table 9. These trials demonstrated good singleagent activity, with median PFS ranging from 4 to 6 months, median OS from 16 to 17 months, and an objective response rate (ORR) ranging from 26% to 41%. Adverse events appeared to be primarily hematologic toxicities, and it was associated with manageable levels of some of the expected chemotherapy-related toxicities, such as alopecia and nausea/vomiting, even in the study by Vogel et al, 52 which included only women who were at least 60 years old. Grade 3/4 peripheral neuropathy was uncommon. 47,51,52 As vinorelbine is a vesicant, painful peripheral phlebitis was seen in a small percentage of patients 51 ; due to this, it is now commonly preferred to administer it through central venous access. 6 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy A CME-Certified Activity

9 Table 10. Eribulin Treatment Results From Phase III Clinical Trials in MBC Endpoint Efficacy Median PFS Median OS EMBRACE Phase III Eribulin vs Physician s Choice Cortes vs 2.2 months (P =.9) 13.1 vs 10.6 months (P =.04) ORR 12% vs 5% (P =.002) Safety Most common AEs from eribulin arm Most common grade 3/4 AEs from eribulin arm asthenia or fatigue 54% neutropenia 52% alopecia 45% peripheral neuropathy 35% nausea 35% neutropenia 45% leukopenia 14% asthenia or fatigue 9% peripheral neuropathy 8% Study 301 Phase III Eribulin vs Capecitabine Kaufman vs 4.2 months (P =.305) 15.9 vs 14.5 months (P =.056) 11% vs 12% (P =.849) neutropenia 54% alopecia 35% leukopenia 31% nausea 22% neutropenia 46% leukopenia 15% peripheral neuropathy 4% AEs = adverse events; ORR = objective response rate; OS = overall survival; PFS = progression-free survival. Bold text denotes efficacy results in eribulin arms. Eribulin, a newer tubulin-binding agent, has a slightly different mechanism of action than vinorelbine, in that it inhibits microtubule polymerization without affecting microtubule depolymerization. 53 It was approved in 2010 for patients who have received at least two prior lines of therapy for MBC, based on results from the phase III EMBRACE trial, 54 in which eribulin was compared with physician s choice of treatment (primarily single-agent chemotherapy) for heavily pretreated patients with MBC. 54,55 This trial demonstrated a 2.5-month improvement in OS with eribulin (Table 10), becoming the first monotherapy regimen in MBC to produce a survival advantage in patients who were previously treated with an anthracycline and a taxane. The eribulin arm also demonstrated a similar safety profile to the control arm. Common toxicities included asthenia or fatigue and neutropenia (Table 10). A subsequent study (301) was conducted to examine the use of eribulin in patients less heavily pretreated, with eligible patients having received 2 prior treatments for MBC. 56 Over 1100 patients were randomized to treatment with eribulin or capecitabine. Although the primary endpoint, demonstration of a PFS or OS advantage with eribulin, was not achieved, eribulin did show a trend toward OS benefit compared with the active monotherapy capecitabine. Of the patients with TNBC, eribulin produced a 14.4-month median survival, compared with a 9.4-month median survival for capecitabine (hazard ratio [HR] = 0.702; P =.01). A recent exploratory retrospective subgroup analysis showed that certain subgroups, including patients with >2 involved organs, progression >6 months after last chemotherapy, and those who had received anthracycline and/or taxane therapies in the metastatic setting, had greater survival benefit from eribulin. 57 Compared with the capecitabine arm, the eribulin arm had a higher incidence of neutropenia (54% vs 16%) but febrile neutro- Table 11. Ixabepilone Treatment Results From Clinical Trials in MBC Endpoint Efficacy Median PFS Phase III Capecitabine ± Ixabepilone Thomas vs 4.2 months (P =.0003) Phase III Capecitabine ± Ixabepilone Sparano vs 4.4 months (P =.0005) Median OS vs 15.6 months (P = 0.1) ORR 35% vs 14% (P <.0001) 43% vs 29% (P <.0001) Phase III* Ixabepilone + Bevacizumab vs Paclitaxel + Bevacizumab Rugo vs 10.6 months (P <.0001) 21 vs 26 months (P =.1) NR 11.5% Phase II Ixabepilone Monotherapy Perez months 8.6 months Safety Most common AEs from ixabepilone arm leukopenia 90% anemia 90% neutropenia 89% peripheral neuropathy 67% hand-foot syndrome 64% thrombocytopenia 54% nausea 53% leukopenia 96% neutropenia 92% anemia 89% peripheral neuropathy 66% hand-foot syndrome 64% thrombocytopenia 59% nausea 51% NR leukopenia 90% anemia 84% neutropenia 79% peripheral neuropathy 60% fatigue/asthenia 50% myalgia/arthralgia 49% alopecia 48% Most common grade 3/4 AEs from ixabepilone arm neutropenia 67% leukopenia 57% peripheral neuropathy 23% hand-foot syndrome 18% neutropenia 72% leukopenia 63% peripheral neuropathy 24% hand-foot syndrome 21% sensory neuropathy 25% fatigue 15% hypertension 11% neutropenia 54% leukopenia 49% peripheral neuropathy 14% fatigue/asthenia 14% AEs = adverse events; MBC = metastatic breast cancer; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival. *This trial also had a nab-paclitaxel arm, which is included in Tables 5 and 6. Bold text denotes efficacy results in ixabepilone-containing arms. A CME-Certified Activity Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy 7

10 penia was low in both arms (2% vs < 1%). Moreover, hand-foot syndrome, a common toxicity with capecitabine (45% in this study), was almost nonexistent in the eribulin arm (0.2%). In the two phase III eribulin studies, peripheral neuropathy was 13%-35% in the eribulin arm, with only 4%-8% grade 3/4 neuropathy. 54,56 A recent quality-of-life analysis from this trial demonstrated that eribulin was associated with greater improvements in overall quality of life (P =.048) and cognitive functioning (P <.001) compared with capecitabine, although capecitabine was associated with greater improvements in emotional functioning (P =.03). 58 Epothilones are microtubule stabilizers with a mechanism of action similar to that of taxanes. 53 However, the epothilone ixabepilone binds to tubulin in a manner different from taxanes that makes it less susceptible to drug resistance. 59 Ixabepilone was approved in 2007 in combination with capecitabine for patients with MBC who no longer receive benefit from an anthracycline or a taxane, 60 based on the phase III CA trial 61 (in Table 11). Results of this trial showed that the addition of ixabepilone to capecitabine produced a 25% reduction in the relative risk of disease progression (median PFS, 5.8 months vs 4.2 months; P =.0003) and it improved absolute response rate by 21% (35% vs 14%; P <.0001). 61 Another trial with a similar design, CA , 62 examined OS as a primary endpoint; although median OS was not significantly different between ixabepilone plus capecitabine vs capecitabine alone (16.4 vs 15.6 months), the addition of ixabepilone did confirm both a PFS advantage (6.2 months vs 4.4 months; P =.0005) and an improved response rate (43% vs 29%; P <.0001). At the time of FDA approval, ixabepilone also earned an indication as monotherapy for those patients whose disease had progressed on not only an anthracycline and a taxane, but also on capecitabine. This indication was based on a phase II trial of ixabepilone monotherapy in that heavily pretreated patient population in which the response rate was 11.5% and the median PFS was 3.1 months. 63 Recently, however, ixabepilone produced disappointing results in combination with bevacizumab in a randomized phase III trial vs paclitaxel plus bevacizumab. 35 The taxane arms of CALGB have already been presented in Tables 5 and 6, but the ixabepilone results are presented in Table 11, which shows that the weekly ixabepilone arm had inferior median PFS compared with weekly paclitaxel (7.6 vs 10.6 months; P <.0001), and median OS that was not significantly different between groups. The main concern with ixabepilone use, however, is its associated toxicities. As shown in Table 11, grade 3/4 neutropenia and leukopenia occurred in one-half to three-quarters of the patients receiving ixabepilone and capecitabine in the phase III ixabepilone trials. 61,62 Even in the phase II monotherapy trial, these toxicities were reduced only modestly, with approximately one-half of the patients experiencing these grade 3/4 toxicities. 63 Grade 3/4 peripheral neuropathy was 14% in the monotherapy trial and 23%-24% in the combination trials. Because of these tolerability concerns, ixabepilone is generally used in later lines of therapy after other, less-toxic agents. Ixabepilone is contraindicated for patients with hepatic impairment due to an increased risk of serious AEs, including toxicity-related deaths. 60 Platinum agents Platinum agents crosslink DNA, disrupting its replication, and thereby preventing cell division. 64 They have been widely used to treat various malignancies, including germ-cell tumors, lung, head and neck, ovarian, and colorectal cancers, but had been less commonly used in breast cancer, perhaps due to the availability of so many other options that were better tolerated. However, they have seen a resurgence of use in the past decade, in parallel with the realization that they may be more active in TNBC, which can have a basal-like gene signature. According to the NCCN guidelines, the platinum agents carboplatin and cisplatin are acceptable single agents for MBC, and carboplatin is listed with gemcitabine as an acceptable combination regimen. 7 In general, carboplatin is used more frequently than cisplatin in the United States for the treatment of breast cancer because it causes less severe nonhematologic toxicities. 65 The available data addressing the role of platinum agents in MBC, however, are limited. No phase III trials have tested platinum agents as monotherapy in MBC, but phase II trials have demonstrated reasonable activity in the first-line setting, with carboplatin response rates ranging from 20%-35% and cisplatin response rates ranging from 47%-54% Some evidence from small neoadjuvant studies suggests that cisplatin has particularly impressive monotherapy activity in TNBC with BRCA mutations Both platinum agents have performed rather poorly in previously treated patients. 74 The combination regimen of gemcitabine and carboplatin has been tested in MBC and was employed as the backbone control in a randomized phase II trial with or without iniparib in patients with TNBC, show- Table 12. Gemcitabine/Carboplatin Treatment Results From Clinical Trials in MBC Endpoint Efficacy Phase II Pretreated TNBC Maisano 2011 Phase II Untreated HER2- Negative MBC Yardley 2008 Phase II HER2-Negative MBC Loesch 2008 Phase II (Control Arm) Unselected TNBC c O Shaughnessy 2011 Phase III (Control Arm) Unselected TNBC c O Shaughnessy 2011 Median PFS 5.5 months 6.4 months 5.5 months a 4.4 months b 3.6 months 4.1 months Median OS 11 months 16.4 vs 15.6 months (P = 0.1) ORR 32% 43% vs 29% (P <.0001) 21.7 months a 7.7 months 11.1 months 11 months b 27% 32% 32% NR Safety Most common grade 3/4 AEs neutropenia 55% thrombocytopenia 32% febrile neutropenia 13% neutropenia 83% thrombocytopenia 86% anemia 31% fatigue/weakness 21% dyspnea 17% febrile neutropenia 10% neutropenia 52% a and 47% b leukopenia 21% a and 23% b thrombocytopenia 10% a and 6% b neutropenia 63% thrombocytopenia 27% anemia 15% fatigue or asthenia 19% leukopenia 10% neutropenia 53% thrombocytopenia 24% anemia 22% AEs = adverse events; MBC = metastatic breast cancer; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TNBC = triple-negative breast cancer. a No taxanes within 2 years; b taxane-pretreated; c control arm of gemcitabine/carboplatin ± iniparib 8 Recent Progress in Metastatic Breast Cancer: Focus on Cytotoxic Therapy A CME-Certified Activity